In general, mild toxicities should prompt evaluation for other causes of the symptoms, and can be managed with symptomatic therapy. Moderate toxicities (four to six stools per day over baseline, abdominal pain, blood in the stool, for example) should prompt withholding of ipilimumab, and treatment with prednisone or an equivalent at 0.5 mg/kg day if the symptoms persist for more than a week.
For severe toxicity (seven or more stools per day over baseline, peritoneal signs along with signs of perforation, ileus, and fever, for example), discontinue ipilimumab; evaluate for bowel perforation; consider endoscopy; and give steroids at 1-2 mg/kg per day until the patient improves, with tapering over a month, he said.
As for other emerging immunotherapy drugs, anti–programmed death-1 (anti-PD-1) antibodies now in development are showing great promise in melanoma. One recent study showed that combining an anti-PD-1 (nivolumab) and ipilimumab was effective for the treatment of advanced melanoma (N. Engl. J. Med. 2013;369:122-33). Concurrent treatment with both agents was associated with a "very encouraging" 53% objective response rate in 53 patients, "albeit with a high rate of grade III/IV toxicity," he said.
"The findings are quite striking in terms of the degree of suppression in tumor measurement," he added, noting that the studies are ongoing.
Compared with targeted therapy for melanoma, which tends to have early and dramatic results, with tumor shrinkage and delayed tumor progression early, but with a plateau over the long term ("the answer is still out" on long-term efficacy, Dr. Thompson noted), immunotherapy tends to have little effect early in the course of therapy but is associated with a "promising tail on the survival curve, where there’s a subset of patients who have very durable response and survival," he said.
A simplified treatment algorithm can be used to help select the appropriate treatment, he added.
For patients with low-volume BRAF wild-type disease (who thus are not thought to be eligible for BRAF-directed therapy), consider clinical trial enrollment or high-dose interleukin-2, ipilimumab, or an anti-PD1 (expected to be available soon, according to Dr. Thompson).
For those with BRAF wild-type and symptomatic bulky disease, the choice is more difficult given the delayed immune response with ipilimumab. Consider a clinical trial; combining cytotoxic agents with an immune checkpoint inhibitor may also be appropriate in these patients, he said.
The decision is also complicated for those with documented BRAF mutation and low-volume disease, as going straight to targeted therapy is an option, but trying an immune checkpoint drug first, and moving to targeted therapy if the patient fails to respond, is also an option.
Targeted therapy is recommended for those with BRAF mutation and bulky disease, he said.
As for patients who have undergone resection for stage 3 or certain high-risk stage 2 disease, the guidelines call for consideration of adjuvant therapy. Interferon is an approved therapy for these patients, but there has been a lot of disagreement among NCCN Melanoma Panel members regarding its use because of the side-effect profile.
A study looking at ipilimumab vs. placebo in these patients is underway, as is a trial comparing low- and high-dose ipilimumab and interferon.
"We are eagerly awaiting the results," he said, noting that other areas of interest with respect to immunotherapy include T-cell therapy (including cells with engineered immune receptors); lymphokines (such as IL-15 and IL-21), either alone or in combination with vaccines or immune checkpoint inhibitors; receptor-directed cytokines; and combinations of targeted agents with immunomodulators.
Dr. Thompson reported receiving grant or research support from Bristol-Myers Squibb, Exelixis, Genentech, and GlaxoSmithKline.